This invention relates to novel sulfonamide substituted diphenyl thiourea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 mediated diseases.
Many different names have been applied to Interleukin-8 (IL8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2 or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROxcex1, GROxcex2, GROxcex3 and NAP-2 also belong to the chemokine family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAxcex1, xcex2 and xcex3 respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor (CXCR2).
IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 stimulate a number of a functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL 8xcex2 receptor (CXCR2). Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rxcex1, which binds only IL8 with high affinity, and IL-8Rxcex2, which has high affinity for IL-8 as well as for GROxcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds, which are capable of binding to the IL-8 xcex1 or xcex2 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein:
R is selected from the group consisting of cyano, OR11, C(O)NR15R16, R18, C(O)OR11, C(O)R11, and S(O)2R17;
Rb is independently selected from the group consisting of hydrogen, NR6R7, OH, ORa, C1-5alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl; cycloalkyl, cycloalkyl C1-5 alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, and a heterocyclic C2-4alkenyl moiety, all of which moieties are optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono and di-C1-4 alkyl substituted amine, ORa, C(O)Ra, NRaC(O)ORa, OC(O)NR6R7, hydroxy, NR9C(O)Ra, S(O)tRa, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)tNR6R7, and NHS(O)tRa; or the two Rb substituents join to form a 3-10 membered ring, and containing, in addition to optionally substituted C1-9 alkyl, independently, 0 to 3 substituents selected from the group consisting of NRa, C(O), O, S, SO, and SO2 moieties which are unsaturated or saturated.
Ra is selected from the group consisting if alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COORa, and a heterocyclic C1-4alkyl moiety, all of which moieties are optionally substituted;
m is an integer having a value of 1 to 3;
mxe2x80x2 is 0, or an integer having a value of 1 or 2;
n is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R1 is independently selected from the group consisting of
hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10alkoxy, azide,S(O)tR4, (CR8R8)qS(O)tR4, hydroxy, hydroxy substituted C1-4alkyl,aryl, aryl C1-4 alkyl, aryl C2-10 alkenyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-10 alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclicC1-4alkyloxy, heterocyclicC2-10 alkenyl, (CR8R8)qNR4R5, (CR8R8)qC(O)NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11,
C2-10 alkenyl C(O)OR11, (CR8R8)qC(O)OR11, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2R13, and (CR8R8)qS(O)2NR4R5, or two R1 moieties together form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring, wherein the alkyl, aryl, arylalkyl, heteroaryl, or heterocyclic moieties are optionally substituted;
R4 and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl; or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which optionally comprises an additional heteroatom selected from the group consisting of O, N and S;
R6 and R7 are independently selected from the group consisting of hydrogen, C1-4 alkyl, heteroaryl, aryl, alkyl aryl, and alkyl C1-4 heteroalkyl; or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring optionally contains an additional heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, which ring is optionally substituted;
Y is selected from the group consisting of hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, azide, (CR8R8)qS(O)tRa, (CR8R8)qORa, hydroxy, hydroxy substituted C1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, arylC1-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heteroaryl C2-10 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclicC2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenylC(O)R11, (CR8R8)qC(O)OR11, C2-10alkenylC(O)OR11, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qNHS(O)tR13, (CR8R8)qS(O)tNR4R5, (CR8R8)qC(NR4)NR4R5, and (CR8R8)qNR4C(NR5)R11; or two Y moieties together form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring; wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are optionally substituted;
R8 is hydrogen or C1-4 alkyl;
R9 is hydrogen or a C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl; and
R13 is selected from the group consisting of C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula (I), may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 xcex1 and xcex2 receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
Suitably, Rb is independently hydrogen, NR6R7, OH, ORa, C1-4alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C1-4alkyl; C1-4 alkyl; amino, mono or di-C1-4 alkyl substituted amine; cycloalkyl, cycloalkyl C1-5 alkyl, ORa; C(O)Ra; NRaC(O)ORa; OC(O)NR6R7; aryloxy; aryl C1-4 oxy; hydroxy; C1-4 alkoxy; NR9C(O)Ra; S(O)mxe2x80x2Ra; C(O)NR6R7; C(O)OH; C(O)ORa; S(O)tNR6R7; NHS(O)tRa; Alternatively, the two Rb substituents can join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 NR9, O, S, SO, or SO2 moities which can be optionally substituted.
Suitably, Ra is an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted.
Suitably R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl, such as CF3; C1-10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; C1-10 alkoxy, such as methoxy, or ethoxy; halosubstituted C1-10 alkoxy, such as trifluoromethoxy; azide; (CR8R8)qS(O)tR4, wherein t is 0, 1 or 2; hydroxy; hydroxy C1-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C1-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C1-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)qC(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)qC(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)qC(O)R11; (CR8R8)qC(O)OR11; (CR8R8)qOC(O)R11; (CR8R8)qNR4C(O)R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)qNR4C(NR5)R11; (CR8R8)qNHS(O)tR13; (CR8R8)qS(O)tNR4R5. All of the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below.
For use herein the term xe2x80x9cthe aryl, heteroaryl, and heterocyclic containing moietiesxe2x80x9d refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term xe2x80x9cmoietiesxe2x80x9d and xe2x80x9cringsxe2x80x9d may be interchangeably used throughout.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
Suitably, R8 is independently hydrogen or C1-4 alkyl.
Suitably, R9 is hydrogen or a C1-4 alkyl;
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, R10 is C1-10 alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
Suitably, R11 is hydrogen, C1-4 alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl.
Suitably, R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.
Suitably, R13 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
Suitably, Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)qS(O)tRa; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic C1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)qC(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)qC(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)qC(O)OR12; (CR8R8)qOC(O)R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)qNR4C(NR5)R11; (CR8R8)qNR4C(O)R11; (CR8R8)qNHS(O)tR13; or (CR8R8)qS(O)tNR4R5; or two Y moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
Suitably s is an integer having a value of 1 to 3.
When Y forms a dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. These ring systems may be substituted 1 to 3 times by other Y moieties as defined above.
Suitably, Ra is an alkyl, aryl C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclic, or a heterocyclicC1-4 alkyl, wherein all of these moieties may all be optionally substituted.
Y is preferably a halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio C1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2xe2x80x2-position or 2xe2x80x2-, 3xe2x80x2-position.
While Y may be substituted in any of the ring positions, n is preferably one. While both R1 and Y can both be hydrogen, it is preferred that at least one of the rings is substituted, preferably both rings are substituted.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d unless specifically defined shall mean such groups as halogen, such as fluorine; chlorine, bromine or iodine; hydroxy; hydroxy substituted C1-10alkyl; (C8R8)qOR4; C1-10alkoxy, such as methoxy or ethoxy; two substituents together may form Oxe2x80x94(CH2)sxe2x80x94O; S(O)mxe2x80x2C1-10 alkyl, wherein mxe2x80x2 is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR4R5 group; NHC(O)R4; C(O)NR4R5; C(O)OR4; S(O)tNR4R5; NHS(O)tR20, C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted C1-10 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C1-10 alkoxy; S(O)mxe2x80x2C1-10 alkyl; amino, mono and di-substituted alkyl amino, such as in the NR4R5 group; C1-10 alkyl, or halosubstituted C1-10 alkyl, such as CF3.
R20 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclicalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfur may be optionally oxidized to the sulfone or the sulfoxide.
xe2x80x9carylalkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
xe2x80x9cwherein two R1 moieties (or two Y moieties) may together form a 5 or 6 membered saturated or unsaturated ringxe2x80x9d is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Illustrative compounds of Formula (I) include:
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3,Nxe2x80x3dimethylaminosulfonyl)phenyl]cyanoguanidine;
N-[4chloro-2-hydroxy-3-(Nxe2x80x3,Nxe2x80x3-dimethylaminosulfonyl)phenyl]-Nxe2x80x2-(2,3-dichlorophenyl)cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl]aminosulfonylphenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl]aminosulfonylphenyl]cyanoguanidine;
N-phenyl-Nxe2x80x2-[4-chloro-2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl[aminosulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4chloro-2-hydroxy-3-[R-(2-methoxymethyl)pyrrolidin-1-yl]aminosulfonylphenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4chloro-2-hydroxy-3-[R-(2-methoxymethyl)pyrrolidin-1-yl]aminosulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-isoxazolidinylaminosulfonylphenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-isoxazolidinylaminosulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-tetrahydroisoxazylaminosulfonyl)phenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-tetrahydroisoxazylaminosulfonyl)phenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(4-thiomorpholinylaminosulfonyl)phenyl]cyanoguanidine;
N-[4-chloro-2-hydroxy-3-[Nxe2x80x3,Nxe2x80x3-dimethylaminosulfonyl]phenyl]-Nxe2x80x2-(2-bromophenyl)propylguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(4-oxidothiomorpholino)amino sulfonylphenyl]cyanoguanidine;
N-(2,3-chlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(4-oxidothiomorpholino)amino sulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-methylpiperazino)amino sulfonylphenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3(Nxe2x80x3-methylpiperazino)amino sulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-ethylmorpholino)amino sulfonylphenyl]cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-(Nxe2x80x3-ethylmorpholino)amino sulfonylphenyl]cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-{4-chloro-2-hydroxy-3-[Nxe2x80x3-ethyl-2-(2-ethylpyrrolidino)]amino sulfonylpheny}cyanoguanidine;
N-(2,3dichlorophenyl)-Nxe2x80x2-{4-chloro-2-hydroxy-3-[Nxe2x80x3-ethyl-2-(2-ethylpyrrolidino)]amino sulfonylpheny)cyanoguanidine;
N-(2-bromophenyl)-Nxe2x80x2-{4-chloro-2-hydroxy-3-[S-(+)-(2-carboxy)pyrrolidin-1-yl]amino sulfonylpheny}cyanoguanidine;
N-(2,3-dichlorophenyl)-Nxe2x80x2-(4-chloro-2-hydroxy-3-[S-(+)-(2-carboxy)pyrrolidin-1-yl]amino sulfonylpheny}cyanoguanidine;
N-(2-bromo-3-fluorophenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl]sulfonylphenyl]cyanoguanidine;
N-(2-phenoxyphenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl]sulfonylphenyl]cyanoguanidine; and
N-(2-benzoxyphenyl)-Nxe2x80x2-[4-chloro-2-hydroxy-3-[S-(+)-(2-methoxymethyl)pyrrolidin-1-yl]sulfonylphenyl]cyanoguanidine;
or a pharmaceutically acceptable salt thereof.
The compounds of Formulas (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. 
a) i) NCS, AcOH, H2O, ii) LiOH, MeOH b) H2SO4, HNO3 c) KOH, MeOH d) PCl5,POCl3 e) NRxe2x80x2Rxe2x80x3H, Et3N f) NaH, H2O g) Pd/C, H2 h)RCNO, DMF i) TBSCl, Imidazole j) MsCl, Et3N k) NH2CN, Hunig""s base 1) CsF/TBAF, MeOH/THF
The desired 4-chloro-N-(3-sulfonamido-2-hydroxyphenyl)-Nxe2x80x3-phenyl cyanoguanidine can be synthesized from the commercially available 2,6-dichloro thiophenol using procedure elaborated in scheme 1. The thiol can be oxidized to the sulfonyl halide using a halogenating agent such as NCS, NBS, chlorine or bromine in the presence of a protic solvent such as alcohol, acetic acid or water. The sulfonyl halide can be hydrolyzed by using a metal hydroxide such as lithium or potassium hydroxide to form the corresponding sulfonic acid salt.
The sulfonic acid salt can then be nitrated under nitration conditions such as nitric acid in a solvent of strong acid such as sulfuric acid to form the nitro phenyl sulfonic acid 3-scheme 1. The sulfonic acid 3-scheme 1 can be converted to the sulfonamide 5-scheme 1 using a three step procedure involving the formation of the metal salt using a base such as potassium hydroxide, sodium hydride or sodium carbonate to form 4-scheme 1. The sulfonic acid salt is then converted to the sulfonyl chloride using PCl5 with POCl3 as a solvent. The sulfonyl chloride can then be converted to the corresponding sulfonamide using the desired amine HNRxe2x80x2Rxe2x80x3 in triethyl amine at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C. to form the corresponding sulfonamide 5-scheme 1.
The chlorine ortho to the nitro group can be selectively hydrolyzed using sodium hydride/water in THF at room temperature to form the phenol. The nitro can be reduced by conditions well known in the art such as hydrogen and palladium on carbon to form the corresponding aniline 6scheme 1. The aniline can then be coupled with a commercially available thioisocyanate to form the desired thiourea.
The phenol in thiourea can be protected with TBSCl to form the corresponding compounds 7-scheme 1. The protected thiourea can be converted to the corresponding carbodiimide 8-scheme 1 using methanesulfonyl chloride and triethyl amine at 0xc2x0 C. The carbodiimde can then be converted to the corresponding protected cyanoguanidine using cyanamide and Hunig""s base, followed by desilylation with CsF or TBAF to form the desired the cyanoguanidine 9-scheme1. 
If the desired hydroxyaniline 6-Scheme 1 is not commercially available, it can be prepared as outlined in Scheme 2: Commercially available substituted 3-chloroanilines 1-scheme-2 can be converted to the amide 2-scheme-2 using standard conditions well known in the art such as pivavolyl chloride and triethylamine in a suitable organic solvent such as methylene chloride. The amide 2-scheme-2 can be converted to the benzoxazole 3-scheme-2 using an excess amount of a strong base such as butyllithium in a suitable organic solvent such as THF under reduced reaction temperatures (xe2x88x9220 to xe2x88x9240xc2x0 C.) followed by quenching the reaction with sulfur dioxide gas and converting resulting sulfinic acid salt to the sulfonyl chloride 3-scheme-2 using standard conditions well known in the art such as sulfuryl chloride in a suitable organic solvent such as methylene chloride. The sulfonyl chloride 3-scheme-2 can be transformed to the sulfonamide 4-scheme-2 using standard conditions well known in the art by reacting it with the amine HN(Rb)2 in the presence of a suitable amine base such as triethylamine in a suitable organic solvent such as methylene chloride. The desired phenolaniline 5 can be obtained from the benzoxazole 4scheme-2 using standard hydrolysis conditions well known in the art such as suilfric acid in water and heating at 85xc2x0 C.